Sivmac is a lymphocytopathic primate lentivirus related to the human immunodeficiency virus (HIV) type 1 and type 2 (closer to HIV-2). Both molecularly cloned and uncloned sivmac infection of macaques results in a fatal aids-like syndrome. Such infection has served as the principal non-human primate model for both HIV infection and aids in humans. Previous observations of protection from SIV disease by vaccination with virulence-attenuated SIV suggest that methods which express SIV proteins within host cells may protect against virulent virus. Genetic vaccination achieves intracellular expression of viral antigens after subgenomic viral gene transfer. Such intracellular antigen expression induces cytotoxic T cell (CTL) and humoral immune responses which are very similar to those elicited by viral infection. Consequently, genetic vaccination of somatic tissues may serve as an alternative to attenuated viral vaccines by mimicking viral infection without replication-competent virus. Previous studies indicated that intramuscular needle injection of DNA coding for influenza viral antigens elicits a protective mixed cellular and humoral immune response in rodents. Primate muscle transfection by needle injection of DNA has proven much less efficient than rodent muscle transfection. This difference in efficiency most likely reflects the increased amount of connective tissue present in primate perimyseum. Our preliminary data demonstrates that the use of a DNA injection device overcomes this decreased efficiency. We are also participating in the development of a respiratory epithelial transfection system. This system can be adapted for oral genetic vaccination by aerosolization of liposome/polynucleotide complexes; such a vaccine protocol may induce a mucosal immune response.